2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 1-(7-Fluoro-2-(6-methoxy-2-pyridinyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

HRID 1618553Notes

Reaction equation

HRID 1618553 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[O:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[C:51]3[NH:53][CH2:54][C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[C:50]3=[CH:49][CH:48]=2)[CH2:43][CH2:42]1.Cl[C:62]1[C:71]2[C:66](=[CH:67][C:68]([F:72])=[CH:69][CH:70]=2)[N:65]=[C:64]([C:73]2[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[N:74]=2)[C:63]=1[CH3:81]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:68]1[CH:67]=[C:66]2[C:71]([C:62]([N:53]3[C:51]4[C:50](=[CH:49][CH:48]=[C:47]([N:44]5[CH2:43][CH2:42][O:41][CH2:46][CH2:45]5)[CH:52]=4)[C:55]4([CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)[CH2:54]3)=[C:63]([CH3:81])[C:64]([C:73]3[CH:78]=[CH:77][CH:76]=[C:75]([O:79][CH3:80])[N:74]=3)=[N:65]2)=[CH:70][CH:69]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672846616-Morpholino-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]HCID 672853724-Chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline

Product 1

HCID 509387201-(7-Fluoro-2-(6-methoxy-2-pyridinyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (26.9 mg, 0.056 mmol), Pd2dba3 (25.9 mg, 0.028 mmol), sodium tert-butoxide (45.4 mg, 0.47 mmol), 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (50 mg, 0.18 mmol) (described herein), and 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (57 mg, 0.19 mmol) (described herein) in toluene (2 mL) was stirred at 100° C. for 18 h, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with saturated aqueous sodium bicarbonate solution, 1 M NaOH, and brine, and the organic layer dried (MgSO4) and concentrated. Column chromatography afforded 1-(7-fluoro-2-(6-methoxy-2-pyridinyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran] as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.75-7.90 (3H, m), 7.55 (1H, dd, J=7.2, 0.8 Hz), 7.22-7.27 (1H, m), 7.11-7.19 (1H, m), 6.85 (1H, dd, J=8.3, 0.9 Hz), 6.30-6.39 (1H, m), 5.64 (1H, d, J=2.2 Hz), 3.93-4.09 (7H, m), 3.67-3.79 (4H, m), 3.48-3.64 (2H, m), 2.91-3.05 (4H, m), 2.39-2.48 (3H, m), 2.09-2.24 (2H, m), 1.90 (1H, dt, J=13.8, 1.1 Hz), 1.76-1.86 (1H, m). Mass Spectrum (ESI) m/e=541 (M+1).

Workup

  1. temperaturecooled to rt
  2. concentrationconcentrated
  3. washwashed with saturated aqueous sodium bicarbonate solution, 1 M NaOH, and brine
  4. dry with materialthe organic layer dried (MgSO4)
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-a97782121cec452cac503e4abeb9d91e
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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